Duowell Mechanism of Action

ATC code: C10BX20.
Pharmacology: Pharmacodynamics: Mechanism of action: Telmisartan: Telmisartan is an orally active and specific angiotensis II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensis II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting.
Rosuvastatin: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.
Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
The safety and efficacy of this drug (telmisartan/rosuvastatin 80/20 mg) was evaluated in a double-blind, randomized, multi-center phase III clinical study in patients with hypertension and hyperlipidemia. Therapeutic lifestyle change (TLC) was performed for 4~12 weeks during the screening period in patients prior to administration of the drug. If applicable, patients were asked to discontinue anti-hyperlipidemic drug completely during the screening period, and anti-hypertensive for at least two weeks before administration of the drug. After the therapeutic lifestyle change period, a total of 210 patients who satisfied the inclusion/exclusion criteria were randomized to the test group (telmisartan/rosuvastatin 80/20 mg: 84 patients), control group 1 (Rosuvastatin 20 mg: 42 patients), control group 2 (Telmisartan 80 mg: 43 patients) and control group 3 (Placebo: 41 patients). The drug was administered once a day for 8 weeks. Among them, the safety was evaluated for 208 patients who were randomized and administered at least 1 dose of the drug, and efficacy was evaluated for 203 patients who measured primary efficacy endpoints more than once. As co-primary efficacy parameters, the changes from baseline in MSDBP and LDL-C after 8 weeks of administration of the drug were evaluated. The telmisartan group (test group and control group 2) showed a statistically superior MSDBP lowering effect compared to non-telmisartan group (control group 1 and 3), and the test group showed a statistically superior MSDBP lowering effect compared to control group 1. The rosuvastatin group (test group and control group 1) showed a statistically superior LDL-C lowering effect compared to non-rosuvastatin group (control group 2 and 3), and the test group showed a statistically superior LDL-C lowering effect compared to control group 2. (See Tables 1 and 2.)

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Pharmacokinetics: A biological equivalence study was conducted to compare the bioavailability of this drug (telmisartan/rosuvastatin 80/20 mg) and co-administration of telmisartan 80 mg and rosuvastatin 20 mg. As a result of measuring the concentrations of telmisartan and rosuvastatin in the blood through a single-dose, 2x2 cross-over study to healthy adults, the 90% confidence interval of the geometric mean ratio of the study drug to the comparator was within 0.80-1.25 for both AUC_last and C_max, satisfying the equivalence criterion.
Other pharmacokinetic profiles such as plasma-protein binding, distribution, biotransformation, and excretion of the Duowell tablet have not been studied separately, but the pharmacokinetic properties of each previously approved ingredient are as follows.
Telmisartan: Absorption: Following oral administration, peak concentrations of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 mg and 160 mg, the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 mg to 160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Distribution: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.
Metabolism and Elimination: Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
Rosuvastatin: Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to the dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin.
Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450/2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. The elimination half-life of rosuvastatin is approximately 19 hours.
Toxicology: Preclinical studies: Telmisartan: In preclinical safety studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit), changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs, renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically-mediated undesirable effects, known from preclinical studies with both angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, were prevented by oral saline supplementation. In both species, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance. No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan an effect on the postnatal development of the offsprings such as lower body weight and delayed eye opening was observed. There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Rosuvastatin: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.
Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with Caucasians. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian and Black groups.